Scott Napier Byrne

Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis ( Mtb ), remains one of the most prevalent infectious diseases worldwide. Despite decades of dedicated efforts to develop effective prevention strategies, including vaccines, TB continues to cause significant morbidity and mortality globally. Beyond the Bacille Calmette–Guérin (BCG) vaccine, limited progress has been made to develop more effective TB vaccines. A better understanding of the immunomodulatory roles of key Mtb protein virulence factors is therefore needed for the development of more efficacious protein‐based vaccine candidates. Herein, we report a highly efficient method for the semi‐synthesis of two native mycobacterial lipoproteins and glycolipoproteins, LprA and Mpt83, respectively. Capitalising on the enhanced reactivity of peptide selenoesters as acyl donors, the 21–23 kDa homogeneously lipidated proteins could be generated in a single ligation step. The homogeneous mycobacterial lipoprotein and glycolipoprotein molecules were shown to be agonists of Toll‐like receptor 2 (TLR2) and led to the potent induction of pro‐inflammatory cytokines and chemokines in cells. Taken together, this work presents a robust semi‐synthetic platform for accessing lipoproteins involved in host–pathogen interactions that can help guide future TB vaccine design.

Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis ( Mtb ), remains one of the most prevalent infectious diseases worldwide. Despite decades of dedicated efforts to develop effective prevention strategies, including vaccines, TB continues to cause significant morbidity and mortality globally. Beyond the Bacille Calmette–Guérin (BCG) vaccine, limited progress has been made to develop more effective TB vaccines. A better understanding of the immunomodulatory roles of key Mtb protein virulence factors is therefore needed for the development of more efficacious protein‐based vaccine candidates. Herein, we report a highly efficient method for the semi‐synthesis of two native mycobacterial lipoproteins and glycolipoproteins, LprA and Mpt83, respectively. Capitalising on the enhanced reactivity of peptide selenoesters as acyl donors, the 21–23 kDa homogeneously lipidated proteins could be generated in a single ligation step. The homogeneous mycobacterial lipoprotein and glycolipoprotein molecules were shown to be agonists of Toll‐like receptor 2 (TLR2) and led to the potent induction of pro‐inflammatory cytokines and chemokines in cells. Taken together, this work presents a robust semi‐synthetic platform for accessing lipoproteins involved in host–pathogen interactions that can help guide future TB vaccine design.

There are several connections between coronavirus disease 2019 (COVID-19), solar UV radiation, and the Montreal Protocol. Exposure to ambient solar UV radiation inactivates SARS-CoV-2, the virus responsible for COVID-19. An action spectrum describing the wavelength dependence of the inactivation of SARS-CoV-2 by UV and visible radiation has recently been published. In contrast to action spectra that have been assumed in the past for estimating the effect of UV radiation on SARS-CoV-2, the new action spectrum has a large sensitivity in the UV-A (315–400 nm) range. If this “UV-A tail” is correct, solar UV radiation could be much more efficient in inactivating the virus responsible for COVID-19 than previously thought. Furthermore, the sensitivity of inactivation rates to the total column ozone would be reduced because ozone absorbs only a small amount of UV-A radiation. Using solar simulators, the times for inactivating SARS-CoV-2 have been determined by several groups; however, many measurements are affected by poorly defined experimental setups. The most reliable data suggest that 90% of viral particles embedded in saliva are inactivated within ~ 7 min by solar radiation for a solar zenith angle (SZA) of 16.5° and within ~ 13 min for a SZA of 63.4°. Slightly longer inactivation times were found for aerosolised virus particles. These times can become considerably longer during cloudy conditions or if virus particles are shielded from solar radiation. Many publications have provided evidence of an inverse relationship between ambient solar UV radiation and the incidence or severity of COVID-19, but the reasons for these negative correlations have not been unambiguously identified and could also be explained by confounders, such as ambient temperature, humidity, visible radiation, daylength, temporal changes in risk and disease management, and the proximity of people to other people. Meta-analyses of observational studies indicate inverse associations between serum 25-hydroxy vitamin D (25(OH)D) concentration and the risk of SARS-CoV-2 positivity or severity of COVID-19, although the quality of these studies is largely low. Mendelian randomisation studies have not found statistically significant evidence of a causal effect of 25(OH)D concentration on COVID-19 susceptibility or severity, but a potential link between vitamin D status and disease severity cannot be excluded as some randomised trials suggest that vitamin D supplementation is beneficial for people admitted to a hospital. Several studies indicate significant positive associations between air pollution and COVID-19 incidence and fatality rates. Conversely, well-established cohort studies indicate no association between long-term exposure to air pollution and infection with SARS-CoV-2. By limiting increases in UV radiation, the Montreal Protocol has also suppressed the inactivation rates of pathogens exposed to UV radiation. However, there is insufficient evidence to conclude that the expected larger inactivation rates without the Montreal Protocol would have had tangible consequences on the progress of the COVID-19 pandemic. Graphical abstract

This assessment by the Environmental Effects Assessment Panel (EEAP) of the Montreal Protocol under the United Nations Environment Programme (UNEP) evaluates the effects of ultraviolet (UV) radiation on human health within the context of the Montreal Protocol and its Amendments. We assess work published since our last comprehensive assessment in 2018. Over the last four years gains have been made in knowledge of the links between sun exposure and health outcomes, mechanisms, and estimates of disease burden, including economic impacts. Of particular note, there is new information about the way in which exposure to UV radiation modulates the immune system, causing both harms and benefits for health. The burden of skin cancer remains high, with many lives lost to melanoma and many more people treated for keratinocyte cancer, but it has been estimated that the Montreal Protocol will prevent 11 million cases of melanoma and 432 million cases of keratinocyte cancer that would otherwise have occurred in the United States in people born between 1890 and 2100. While the incidence of skin cancer continues to rise, rates have stabilised in younger populations in some countries. Mortality has also plateaued, partly due to the use of systemic therapies for advanced disease. However, these therapies are very expensive, contributing to the extremely high economic burden of skin cancer, and emphasising the importance and comparative cost-effectiveness of prevention. Photodermatoses, inflammatory skin conditions induced by exposure to UV radiation, can have a marked detrimental impact on the quality of life of sufferers. More information is emerging about their potential link with commonly used drugs, particularly anti-hypertensives. The eyes are also harmed by over-exposure to UV radiation. The incidence of cataract and pterygium is continuing to rise, and there is now evidence of a link between intraocular melanoma and sun exposure. It has been estimated that the Montreal Protocol will prevent 63 million cases of cataract that would otherwise have occurred in the United States in people born between 1890 and 2100. Despite the clearly established harms, exposure to UV radiation also has benefits for human health. While the best recognised benefit is production of vitamin D, beneficial effects mediated by factors other than vitamin D are emerging. For both sun exposure and vitamin D, there is increasingly convincing evidence of a positive role in diseases related to immune function, including both autoimmune diseases and infection. With its influence on the intensity of UV radiation and global warming, the Montreal Protocol has, and will have, both direct and indirect effects on human health, potentially changing the balance of the risks and benefits of spending time outdoors. Graphical abstract

The ability of ultraviolet radiation to suppress the immune system is thought to be central to both its beneficial (protection from autoimmunity) and detrimental (carcinogenic) effects. Previous work revealed a key role for lipids particularly platelet-activating factor and sphingosine-1-phosphate in mediating UV-induced immune suppression. We therefore hypothesized that there may be other UV-induced lipids that have immune regulatory roles. To assess this, mice were exposed to an immune suppressive dose of solar-simulated UV (8 J/cm²). Lipidomic analysis identified 6 lipids (2 acylcarnitines, 2 neutral lipids, and 2 phospholipids) with significantly increased levels in the skin-draining lymph nodes of UV-irradiated mice. Imaging mass spectrometry of the lipids in combination with imaging mass cytometry identification of lymph node cell subsets indicated a preferential location of UV-induced lipids to T cell areas. In vitro co-culture of skin-draining lymph node lipids with lymphocytes showed that lipids derived from UV-exposed mice have no effect on T cell activation but significantly inhibited T cell proliferation, indicating that the lipids play an immune regulatory role. These studies are important first steps in identifying novel lipids that contribute to UV-mediated immune suppression.

Objectives: The role of innate lymphoid cells (ILC), particularly helper ILC, in the pathogenesis of multiple sclerosis (MS) is not well understood. Here, we present a comprehensive analysis of peripheral ILC subsets in MS patients prior and after alemtuzumab administration using mass cytometry.Methods: Circulating ILC were analysed by mass cytometry in MS patients before and after alemtuzumab. These were compared with non‐MS controls. MS‐related shifts among ILC immunophenotypes were further elucidated by fast interpolation‐based t‐SNE (Flt‐SNE) dimensionality reduction.Results: Neither natural killer (NK) cells nor helper ILC (ILC1, ILC2 and ILC3) levels were altered following alemtuzumab treatment. However, CD56^bright NK cell expansions were observed in relapsing patients. MS patients prior to alemtuzumab further displayed proportional shifts from ILC1 to ILC2, with MS‐associated decreases in CCR6⁺ helper ILC proportions.Conclusion: CD56^bright NK cells during relapse indicate an immediate response to disease reactivation, while CCR6‐related shifts among helper ILC suggest altered ILC migration to the CNS during MS.

Current vaccines against SARS-CoV-2 substantially reduce mortality, but protection against infection is less effective. Enhancing immunity in the respiratory tract, via mucosal vaccination, may provide protection against infection and minimise viral spread. Here, we report testing of a subunit vaccine in mice, consisting of SARS-CoV-2 Spike protein with a TLR2-stimulating adjuvant (Pam₂Cys), delivered to mice parenterally or mucosally. Both routes of vaccination induce substantial neutralising antibody (nAb) titres, however, mucosal vaccination uniquely generates anti-Spike IgA, increases nAb in the serum and airways, and increases lung CD4⁺ T-cell responses. TLR2 is expressed by respiratory epithelia and immune cells. Using TLR2 deficient chimeric mice, we determine that TLR2 expression in either compartment facilitates early innate responses to mucosal vaccination. By contrast, TLR2 on hematopoietic cells is essential for optimal lung-localised, antigen-specific responses. In K18-hACE2 mice, vaccination provides complete protection against disease and sterilising lung immunity against SARS-CoV-2, with a short-term non-specific protective effect from mucosal Pam₂Cys alone. These data support mucosal vaccination as a strategy to improve protection in the respiratory tract against SARS-CoV-2 and other respiratory viruses.

B cells play a major role in multiple sclerosis (MS), with many successful therapeutics capable of removing them from circulation. One such therapy, alemtuzumab, is thought to reset the immune system without the need for ongoing therapy in a proportion of patients. The exact cells contributing to disease pathogenesis and quiescence remain to be identified. We utilized mass cytometry to analyze B cells from the blood of patients with relapse‐remitting MS (RRMS) before and after alemtuzumab treatment, and during relapse. A complementary RRMS cohort was analyzed by single‐cell RNA sequencing. The R package “Spectre” was used to analyze these data, incorporating FlowSOM clustering, sparse partial least squares‐discriminant analysis and permutational multivariate analysis of variance. Immunoglobulin (Ig)A⁺ and IgG₁⁺ B‐cell numbers were altered, including higher IgG₁⁺ B cells during relapse. B‐cell linker protein (BLNK), CD40 and CD210 expression by B cells was lower in patients with RRMS compared with non‐MS controls, with similar results at the transcriptomic level. Finally, alemtuzumab restored BLNK, CD40 and CD210 expression by IgA⁺ and IgG₁⁺ B cells, which was altered again during relapse. These data suggest that impairment of IgA⁺ and IgG₁⁺ B cells may contribute to MS pathogenesis, which can be restored by alemtuzumab.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a summary of the research conducted by the recipients of the 2020 GRAPPA Research Awards was presented by the awardees. The summary of the 4 presentations is provided here.